Monoaminerqic systems are involved in the regulation of mood and provide important sites of action of antidepressant drugs. The present studies concern how the central monoaminergic systems can be modified by prolonged treatment with tricyclic and non-tricyclic antidepressant drugs, by lithium treatment and by electroconvulsive shock treatment as well as the steroid hormones and thyroid hormones. In particular, we will investigate the 5-HT systems which constitute a unique feature of the raphe areas of the brain stem and which appear to be involved in negative reinforcement mechanisms. Studies will also be carried out to determine how the various 5-HT pathways may be controlled GABAergic and various peptidergic neuron systems and to determine the effects of chronic administration of tricyclic antidepressant drugs on the 5-HT nerve cell body containing rape nuclei using stereological principles and a new photographic technique to measure monoamine fluorescence. Among the antidepressant drugs to be studied are amitriptyline, nortriptyline, imipramine, iprindo, nomifensine and zimelidine. Transmitter level, synthesis, release and turnover will be studied with biochemical and histochemical techniques and receptor pharmacology in principle assessed by measurement of ligand binding and transmitter activated adenylate cyclase activity. 5-HT dependent behaviors will also be studied and activated measurements of adenohypophyseal hormones will be made in order to be able to correlate the pre- and postsynaptic changes occuring in the monoaminergic synapeses with biological activity. This interdisciplinary approach is directed towards a better understnading of the central systems involved in regulation of mood and the responsiveness of these systems to drugs which are used in the treatment of depression.